rs587777829

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong

The NM_024649.5(BBS1):​c.432+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000137 in 1,458,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BBS1
NM_024649.5 splice_donor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.95
Variant links:
Genes affected
BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15263748 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-66514679-G-A is Pathogenic according to our data. Variant chr11-66514679-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66514679-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BBS1NM_024649.5 linkuse as main transcriptc.432+1G>A splice_donor_variant ENST00000318312.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BBS1ENST00000318312.12 linkuse as main transcriptc.432+1G>A splice_donor_variant 1 NM_024649.5 P1Q8NFJ9-1
ENST00000658548.1 linkuse as main transcriptn.1530C>T non_coding_transcript_exon_variant 2/2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458352
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
725700
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This sequence change affects a donor splice site in intron 4 of the BBS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). This variant is present in population databases (rs587777829, gnomAD no frequency). Disruption of this splice site has been observed in individuals with Bardet-Biedl syndrome (PMID: 12118255; Invitae). ClinVar contains an entry for this variant (Variation ID: 12145). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterliterature onlyCounsylMar 12, 2014- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 04, 2022Variant summary: BBS1 c.432+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247266 control chromosomes. c.432+1G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Bardet-Biedl Syndrome (example, Mykytyn_2002, Zampaglione_2020, Guardiola_2021). Additionally we have observed this variant as a compound heterozygous genotype in an individual undergoing evaluation for Bardet-Biedl Syndrome at our laboratory. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Bardet-Biedl syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 23, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2002- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 21, 2024Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12118255, 34526762, 32037395, 32349990) -
BBS1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 28, 2024The BBS1 c.432+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous state in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255; Saeed et al. 2020. PubMed ID: 32349990). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt consensus GT splice donor sites in BBS1 are expected to be pathogenic. In summary, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
D;D;D;D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.98
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777829; hg19: chr11-66282150; API